Visceral leishmaniasis [VL] is endemic throughout much of the world [Europe, Central and South America, Africa, Asia] [1]. Drug treatment exists for VL, although it is not always effective and side effects are problematic. Consequently, alternative approaches for the control of this disease are still needed. However to date, murine model VL vaccine studies have failed to demonstrate the levels of protection that have been found for cutaneous leishmaniasis. This proposal is directed towards the development of an effective vaccine against visceral leishmaniasis. The Specific Aims are: Specific Aim 1: Characterization in the Intradermal/Subcutaneous Infection Model of Murine Visceral Leishmaniasis. The ID/SC murine model (new) allows the investigation of the immunological and inflammatory events critical to the initiation and establishment of visceral leishmaniasis through cutaneous infection. Specific Aim 2: Investigate the Potential Biological Mechanisms that Prevent Optimal Protection Found in the Murine VL Vaccine Model. The relatively low level of protection achieved in vaccine studies of VL contrasts to experimental cutaneous leishmaniasis and could be due to a number of parameters (potentially interactive), including: a) the high infective dose employed for infection; b) the route of infection; c) inadequate induction of immunologic effector mechanisms in the current vaccination protocols. These possibilities will be examined. Specific Aim 3: Evaluate the Effectiveness of Immunization with L. infantum Antigens (GP46, Ldp23, D-6, D-14) in Inducing Protection Against Infection and the Potential of a Recombinant Vaccinia Virus/DNA Combination Vaccine. Currently for VL a limited number of vaccine candidates and delivery systems have been explored. These experiments are directed towards the identification and optimization of effective vaccine candidates and delivery systems for VL.